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1

High-dilution effects revisited. 2. Pharmacodynamic mechanisms

Paolo Bellavite,1*

Marta Marzotto,1 Debora Olioso,

1 Elisabetta Moratti,

1 Anita Conforti

2

Homeopathy 103 (2014), pp. 22-43 DOI: 10.1016/j.homp.2013.08.002

1. Department of Pathology and Diagnostics, University of Verona, Strada Le Grazie 8, 37134Verona,

Italy

2. Department of Public Health and Community Medicine, University of Verona, Piazza L.A. Scuro 10,

37134 Verona, Italy

*To whom correspondence should be addressed:paolo.bellavite@univr.it

This is a text+figures version whose online publication in website is authorized

Abstract

The pharmacodynamics aspects of homeopathic remedies are appraised by laboratory studies on

the biological effects at various levels (cellular, molecular and systemic). The major question is how

these medicines may work in the body. The possible answers concern the identification of biological

targets, the means of drug-receptor interactions, the mechanisms of signal transmission and

amplification, and the models of inversion of effects according to the traditional “simile” rule. These

problems are handled by two experimental and theoretical lines, according to the doses or dilutions

considered (low-medium versus high dilutions). Homeopathic formulations in low-medium dilutions,

containing molecules in the range of ultra-low doses, exploit the extreme sensitivity of biological

systems to exogenous and endogenous signals. Their effects are interpreted in the framework of

hormesis theories and paradoxical pharmacology. The hypotheses regarding the action mechanisms of

highly diluted/dynamized solutions (beyond Avogadro-Loschmidt limit) variously invoke sensitivity to

bioelectromagnetic information, participation of water chains in signalling, and regulation of bifurcation

points of systemic networks. High-dilution pharmacology is emerging as a pioneering subject in the

domain of nanomedicine and is providing greater plausibility to the puzzling claims of homeopathy.

Introduction

Homeopathy is progressively receiving scientific validation but a series of theoretical and

technical questions need still to be clarified, since several problems appear to distinguish this discipline

from conventional pharmacology. The physicochemical nature of the homeopathic remedies, which are

produced according to a peculiar method of serial dilution followed by “dynamization”, was dealt with

in a previous paper.1 Here the recent advances concerning the possible mechanism of actions of these

drugs in the body are reviewed. Pharmacokinetics is the branch of pharmacology dedicated to the

determination of the fate of substances administered to a living organism up to the point at which they

are completely eliminated from the body. This approach is often studied in conjunction with

pharmacodynamics, the study of effects on the body. Highly diluted medications, including those

produced according to the homeopathic pharmacopoeia, are hardly suitable to pharmacokinetic

2

investigation, due to the lack of analytical methods having sufficient sensitivity. On the other hand,

experimental evidence from clinical and laboratory studies is providing a remarkable contribution to

pharmacodynamics of this class of remedies. The question of how these medicines may work concerns

the identification of biological targets at various levels (cellular, molecular and systemic), the ways of

drug-receptor interactions, the mechanisms of signal transmission and amplification, and the “simile”

rule (see Table 1). All these problems have several aspects, that can be considered according to the

different doses and/or dilutions employed.

Table 1. Aspects of homeopathic pharmacodynamics

Aspect Medium potencies

(Ultra-Low Doses)

High potencies

(High Dilutions)

Nature of the medicine*

Very low concentrations of active

molecules

Nanoparticles

Nanoparticles

Water clusters

Coherence domains

Biological

targets

Local

Molecular interactions:

- cell receptors

- enzyme activation/regulation

- gene expression

Nonlinear dynamics (bifurcation

points):

- cell receptors

- enzyme activation/regulation

- gene expression

Systemic Neuroimmunologic networks

Neuroimmunologic networks

Disease dynamics (attractors-

miasms)

Bioelectricity (ECG, EEG)

Amplification mechanisms

Cell responsiveness:

- receptor priming

- signal transduction

- stochastic resonance

Enzyme activity:

- allosteric activation

- silica nanostructures

Neuroimmunologic networks

Nonlinearity-chaos

Grotthus-type water chains

Information transfer Molecular interactions

Water chains

Frequency-coded signals

Water chains

Water nanoparticles

Bioelectromagnetics

Inversion of effects

(the “Simile”)

Hormesis

Dual receptors

Gating by cyclic AMP

Heat-shock proteins

Paradoxical pharmacology

Rebound in time

Systems biology theories

Coherent response to stress

*This aspect was the subject of the preceding paper1

Pharmacologic activity of Mother Tinctures and of low potencies (e.g. 2C -3C, containing

relatively high doses of active principles) poses no problems of interpretation and requires analysis of

the components and identification of their targets in the organism, in a way not dissimilar from that of

herbal products, snake toxins, or mineral oligoelements. The action of medium potencies, that contain

ultra-low doses of active principles (ULDs, namely from 4C-5C to approximately 12C, near by the

Avogadro-Loschmidt limit) entails high sensitivity of living organisms and inversion of drug effects, in

the framework of models not much distant from modern pharmacology, like hormetic mechanisms. The

action of high dilutions (HDs, namely homeopathic dilutions beyond the Avogadro-Loschmidt

constant) requires the identification of possible “non molecular” or “meta-molecular” information

transfer mechanisms. Finally, the “holistic” approach of homeopathy as healing system goes far beyond

the identification of specific information transfer mechanisms or molecular targets and should be

understood in the light of systems biology.

3

Biological targets

The specificity of any drug effect is based on the interaction or active principles with their

biological targets and the same can be conceived for homeopathic drugs. In the latter case, the

identification of these interactions is complicated by several factors, including the different nature of

remedies in low and high potencies, the presence of many active principles in most compounds of

vegetal or animal sources, and the different sensitivities that presumably exist in healthy and sick

organisms. In spite of these problems, experimental evidence gathered in laboratory studies has

identified a representative number of cell and molecular targets of homeopathic drugs.

Local targets The cornerstone of homeopathy that the whole clinical picture is considered on an individual basis

is not in dispute, but laboratory models show that mechanism(s) of action of the drug can be

investigated in animals, cells, tissues, and even at the molecular level. Pharmacodynamic effects of

homeopathic remedies have been proven in several dozens of animal and “in vitro” laboratory studies.

Apart from reviews on this topic,2-5

some recent demonstrations of these effects merit to be mentioned.

One of the most interesting lines of research regarded histamine and other compounds (Lung histamine

and Apis mellifica), which have pro-inflammatory effects when used at high doses but trigger anti-

inflammatory mechanisms when employed at ULDs and HDs. The effect of Lung histamine (5C and

15C) and Apis mellifica (9C), traditional remedies used for the treatment of allergic diseases, was

assessed on in vitro human basophil degranulation.6

After this early study, several independent

laboratories reported a significant inhibition of basophil functions by high dilutions of histamine. Most

studies were positive7-14

with few exceptions.15,16

The effect was inhibited by histamine H2 receptor

antagonists cimetidine,17

supporting the hypothesis that high dilutions of histamine exert their inhibitory

power at the level of H2 receptors of basophilic cells. That homeopathic drugs may act through

modulation of cell receptors and protein synthesis is supported also by studies from Khuda-Bukhsh

laboratory.18

In a model of chemically induced murine papilloma, where a known set of proteins

involved in the tumor development were altered, the researchers found a significant remodulation

towards normal condition after treatment with the potentized drug Secale cornutum 30C, driven by the

downregulation of aryl hydrocarbon receptor, as evaluated by western blot analysis.

A large series of studies by an Austrian group19-21

showed the influence of highly diluted thyroxine

(30D) on the spontaneous tendency of juvenile frogs, at the end of metamorphosis, to leave the water

and climb onto land. Climbing activity diminished under the influence of dilution thyroxine 30D, with

statistical significance. These results show that HDs of thyroid hormones, that at physiologic doses

stimulate growth and metamorphosis, transmitted inhibitory information to the same test system, even

though the molarity was beyond Avogadro's constant. This effect was confirmed by independent

laboratories, with various experimental approaches 22-24

Evidence from laboratory,25

animal,26

and clinical27

studies showed that the immune system,

inflammation mechanisms and leukocytes are among the targets of homeopathic effects. Low potency

formulations composed by Arnica montana 4D, Calendula officinalis 4D, Hypericum perforatum 4D

and Symphytum officinale 6D, clinically used for wound healing, exerted in vitro stimulation of

fibroblasts, which are the cells responsible of connective tissue repair.28

Another low potency

formulation containing Arnica montana and other plant extracts and minerals was tested on an animal

model of traumatic inflammation.29

The decrease of paw oedema, associated with the process of

healing, was more rapid in drug-treated than in placebo-treated treated rats and the therapeutic effect

was associated with a significant decrease of interleukin-6. The efficacy of the complete formulation

was higher than the combination of a selection of active components, suggesting that its effect cannot

be considered as the 'sum' of its active components and probably a synergistic interaction occurs to

determine the final effect. The effects of Arnica montana 6C on the modulation of acute inflammation

kinetics in rats were evaluated by another group.30

Medium (6C) and high (12C, 30C, 200C) potencies

of Mercurius solubilis added to mice's drinking water for 7 days (in vivo treatment) modulated

macrophage functions.31

Similar effects were observed also when the same drug was added to the cell

culture, suggesting that the observed “in vivo” effect was due to a direct interaction with macrophages.

Interestingly, another group used Mercurius solubilis in a rat model of wound healing, showing that rats

treated for 21 days with a 12C potency had less wound infections than placebo-treated rats.32

In animal

4

models, also Silica, which is a stimulant of macrophages and fibrous tissue formation at high doses,

stimulates tissue healing and macrophage activation also at extremely low (homeopathic) doses.33,34

Ignatia, Gelsemium, Chamomilla (in homeopathic dilutions/potencies) have consistently shown to

act on the nervous system and specifically to modulate anxiety-like behaviours in rodents.4

In the

traditional Materia Medica and homeopathic literature, Gelsemium is described as a remedy for a

variety of anxiety-like psychological and behavioural symptoms.35-38

All parts of the plant contain the

major active principle gelsemine as well as other toxic strychnine-related alkaloids, such as gelseminine

and sempervirine.39,40

The anxiolytic, antidepressant and/or analgesic action of Gelsemium extracts and

of gelsemine has been recently demonstrated in animal models.4,41-44

A hypothetical target of

Gelsemium has been suggested by studies showing that gelsemine stimulates the biosynthesis of

allopregnanolone (an anti-stress neurosteroid) in the rat brain,45,46

but probably other mechanisms of the

pharmacodynamic action may exist.4 The effects of Gelsemium are not restricted to the nervous system,

as shown by other reports indicating that this plant species may exhibit anticancer and

immunomodulation activity.47-50

The "Gelsemium model" - encompassing experimental studies in vitro

and in vivo from different laboratories and with different methods, including significant effects of its

major active principle gelsemine - may play a pivotal rule for investigating the pharmacodynamics

mechanisms of homeopathic remedies.

Effects on gene expression The ability of high diluted compounds to modulate gene expression in human and unicellular

organisms has been object of investigations. In early studies with the isopathic model of arsenicum-

intoxicated mice, the failure to express the protective effect of Arsenicum album 30C and 200C in the

presence of the transcription blocker Actinomycin D51

suggested that potentized homeopathic drug

acted through active gene transcription. Then, in experiments conducted in biological models (arsenite

or UV treated E. coli and Saccharomyces culture) the treatment with Arsenicum album 30C or Arnica

montana 30C modified the expression of specific genes that are target respectively of the arsenite and

UV irradiation injure.52,53

In recent studies, the same group evidenced the anti-tumorigenic effects of

mother tincture drugs (quercetin, gingerol and Hydrastis canadensis), as demonstrated by the

modulation of the expression of specific mRNA markers of apoptosis and by cell viability tests.

Moreover, they demonstrated a direct interaction between the cell DNA and the drug itself, as observed

by CD spectropolarimetric study and DNA melting analysis.50,54,55

These findings support the

hypothesis that homeopathic remedies could turn on or off some relevant genes, initiating a cascade of

gene actions to correct the gene expression that went wrong to produce the disorder or disease. In this

hypothesis the target relevant gene should be sensitive to similar stimuli and exert a pleiotropic

transcriptional regulation on a battery of genes with correlated functions.

The analysis of gene expression was performed on large-scale by some authors, using the

microarray technique. This method is based on microscopic arrays of immobilized nucleic acids (about

15-30000 genes depending on the type of platform), that function as probes for sequence-specific

nucleic acid hybridization. De Oliveira et al.56

investigated the effects of a complex homeopathic

medication (Aconitum 11D, Thuya 19D, Bryonia 18D, Arsenicum 19D and Lachesis 18D) on cytokine

production and gene expression from mice macrophages. They found that the verum-treated group

differentially expressed 147 genes (45 upregulated and 102 downregulated) when compared to the

placebo-treated group. These genes are mainly involved in transcription/translation, cell structure and

dynamics, immune response, cytoprotection, enzymatic process, and receptors/ligands.

Bigagli and coworkers evaluated the effects of extremely low copper concentrations (from 10−6

to

10−17

M) on gene expression profiles of a line of human prostate epithelial cells.57

Microarray data

demonstrated that copper added to the medium varied gene expression at all concentrations tested.

Unfortunately, the authors did not declare if the solutions were succussed after dilution and if can be

considered as homeopathic preparations. However, an interesting indication is that the effect was not

dose-dependent, but followed a sinusoidal behaviour, since about 12.5%, 14%, 5.5%, 15% and 7.5% of

the genes were modulated by copper 10-6

M, 10-9

M, 10-12

M, 10-13

M and 10-17

M, respectively. Moreover,

there were clusters of genes overexpressed or down-regulated at all concentration and other clusters that

were up-regulated only in the low or high range on copper dilutions.

A recent study proved the effects of homoeopathic medicines (Ruta 200C, Carcinosinum 200C,

Hydrastis 200C, Thuja 200C) on Dalton’s lymphoma tumor cells.58

In particular they measured the

apoptosis and the expression of specific genes, by RT-PCR and microarray. In these experiments

5

dynamized preparations showed significant cytotoxic action against cancer cell lines, and at times, the

activity was higher for 200C potency than for the mother tincture. By the RT-PCR method, the

expression of the apoptotic genes p53, Bcl-2, and caspase 3 after incubation with the ultradiluted

remedies was investigated. Not all the potentized drugs induce expression of all the marker genes, but

only Carcinosinum 200C induced p53 gene expression. Moreover, microarray analysis showed a direct

action of ultradiluted solutions on gene expression: about 100 genes were differentially expressed with

the potentized drugs, while about 600 with Thuya 1M, compared to controls. A comparison of

potentiated drugs with their mother tincture indicated that the potentiated drugs have biological activity

similar to that of their mother tincture in spite of ultradilution.

Our preliminary results reveal the extremely high sensitivity of human neurocytes gene network to

ULDs and HDs of Gelsemium.59

As observed by microarray technique, the drug modulates the

expression of a series of genes involved in neuronal function compared to the control vehicle solution.

24 h exposure to the Gelsemium s. 2C dilution (the lowest potency employed, corresponding to a

gelsemine concentration of 6.5x10-9

M) significantly changed the expression of 56 genes, of which 49

were downregulated and 7 were overexpressed. Several of the downregulated genes belonged to G-

protein coupled receptor signalling pathways, calcium homeostasis, inflammatory response, and

neuropeptide receptors. Several genes significantly decreased their expression even after treatment with

higher dilution/dynamization (3C, 4C, 5C, 9C and even 30C), although with smaller changes (Marzotto

et al, manuscript in preparation).

Systemic targets The existence of specific cell and molecular targets for drugs does not mean that the homeopathic

effects can be explained by local interactions only. Although homeopathy is thought to have been born

as an empirical approach, it is actually based on a systemic and dynamic view of health and disease,

that can be better appreciated inside the new paradigm of complex systems,60-65

whose key features are:

a) Non-linearity: output is not proportional to input, occurrence of paradoxical responses; b)

deterministic chaos: apparently unpredictable behaviour, sensitivity to initial values and perturbations,

fractals, self-similarity; c) emergence: self-organization, pattern formation, coherence, oscillations,

dynamic attractors; d) adaptation: evolution, plasticity, memory and learning, hysteresis,

sensitization/desensitization, tolerance. These concepts of nonlinear dynamics offer a different

perspective for understanding homeodynamics and disease,66-68

and nonlinear system theories are

starting to be applied to help interpret, explain, and predict biological phenomena.69

When a stimulus is applied to complex networks in the immune, endocrine and nervous systems,

the entire network responds and undergoes an adaptation. Such a system is deterministic but extremely

sensitive to even small perturbations. The triggers that cause the immune response to go in a certain

direction depend not just on a single signal, but rather on a multiplicity of elements acting on each other

synergistically, antagonistically and through feedback loops.70

These features can also be used for the

control of chaos and this may open up an avenue for therapy, but further models still need to be refined

and developed.

There is some evidence that HDs applied on the tongue trigger rapid electrophysiological

responses in central nervous system.71,72

Rats kept on a high-salt diet were anesthetized and a

microelectrode, connected up to an oscilloscope, was implanted in the lateral hypothalamic area to

record the discharge frequency in that area. After a suitable period recording the basal tracing, a few

drops of Natrum muriaticum (sodium chloride or common sea salt) 30C or 200C were deposited on the

tongues of the rats. The application caused marked changes (reductions) in the discharge frequency of

the nerve centre. This experiment suggests both that the action of the drug can be mediated by the

hypothalamic nerve centres and that preconditioning with a high-salt diet makes the animal more

sensitive to the remedy Natrum muriaticum. Rapid (few seconds) hypothalamic electrophysiological

responses to Nux vomica 200C and 1000C in ethanol-intoxicated rats were also reported.72

Frequency-coded signals In biology, information transfer does not depend only on the dose of a signal molecule, but also on

the “way” molecules relate to the receiver systems. For example, cells are capable of distinguishing the

kinetics by which a signal is received, i.e., whether it is a sudden signal or one with a slow onset,

whether the concentration is stable or oscillating, whether the signal occurs on its own or is

accompanied by other concomitant or preceding signals, whether it is the first prompting or a repetition

of something previously experienced. Thus, the information is not merely quantitative, but inherently

6

spatiotemporal. Calcium and other intracellular messengers perform their regulating functions by means

of oscillations of concentration which constitute a kind of “digital code” for the various systems

sensitive to them. Such digitally encoded signals could more precisely regulate cell responses also

through rhythmic changes in hormone concentrations.

Biological communication is so important that nature has gone out of its way to devise a wide

variety of forms of communication. To those previously mentioned we can add others, first and

foremost among which are the sense organs endowed with photoreceptors, chemoreceptors,

baroreceptors, and others. Bioelectrical signals, encoded in spatiotemporal changes of membrane

potential, regulate cell proliferation, migration, differentiation, and morphogenesis.73

Sensitization to

chemical toxins includes bioelectric disorders and autonomic changes that can be revealed by spectral

electroencephalography, blood pressure, heart rate, and plasma beta-endorphin.74

In order to create a scientific basis of homeopathy and other complementary medicine applications

like acupuncture, it is certainly necessary to add a more non-local approach. A possible frame concerns

oscillatory electromagnetic interactions as regulatory and - in case of disease - deregulatory impulses of

the organisms.75

A homeopathic stimulus (Strophantus hispidus 30C) changed the power spectrum of

heart rate variability in healthy human subjects during 24-h long intervals.76

Subsequently the same

group used electroencephalography (EEG) to experimentally investigate the effects of HDs in

laboratory rats.77-79

They tested the effects of Coffea cruda 30C and 200C versus placebo on the sleep

patterns of rats assessed using EEG readings in the Delta band, 0.5-2.5 Hz, from the parietal region.

Treatments were administered orally at the beginning of the sleeping period. In synthesis, the spectral

power of Delta band was significantly higher than baseline for Coffea 30C and caffeine (15.5 mg/kg).

Coffea 30C and caffeine have similar effects on sleep pattern, enhancing delta power; Coffea 200C

appeared to affect only the synchronization. Another interesting study regarded histamine.80

Besides

being an inflammation mediator, histamine is a central neurotransmitter, it increases arousal via H1

receptors. HDs of histamine (30C) decreased the mean Delta band spectral density and the effect was

very rapid. Subsequently the same group tested different potencies and found highly non-linear patterns,

with peaks of activity at 15C, 21C and 30C dilutions.81

Following those animal studies, remedy-related sleep stage alterations and EEG changes were

detected in human subjects. In patients with fibromyalgia, the clinical response to homeopathic

remedies at a systemic level is associated with changes in prefrontal electroencephalographic alpha

frequency cordance (EEG-C, a correlate of functional brain activity).82

In a recent experimental trial,

college students with a history of coffee-related insomnia took one bedtime dose of a homeopathic

remedy (Coffea cruda or Nux vomica 30C) and those remedies significantly altered short-term nonlinear

dynamic parameters of slow wave sleep.65

These observations suggest EEG-C as an early biomarker of

individualized homeopathic medicine effects. Recently, the same group used electroencephalography to

evaluate psychophysiological effects of two homeopathic remedies (Sulphur or Pulsatilla) after an

olfactory activation protocol on healthy young adults.83

The data showing significant interactions of remedies for EEG parameters encourage additional

research on nonlinear psychophysiological and bioelectric effects of homeopathic remedies.

Disease dynamics and bifurcation points The ability of extremely diluted drugs to change the behaviour of cells, animals and humans can

be ascribed to the high sensitivity of the targets involved and to the existence of subtle bifurcation

points in the disease dynamics. For example, we have shown that Gelsemium sempervirens may

modulate anxiety in mice, because tests which are designed to put the animal in a situation of

uncertainty, regarding the trajectory of movements in an open space.84

In this situation, an extremely

slight pharmacological influence on emotional state of the animal can determine the choice of which

direction to move, e.g. of whether the animal moves toward the open space or along the walls of the test

platform. The sensitivity of laboratory tests (and humans in clinical settings) to minimal factors is also,

conceivably, one reason for the high variability of responses in the various experiments and of the

experienced difficulties in full replicability in different laboratories.

Far from equilibrium states and bifurcation points are found at each level of the disorganization of

living organisms, from molecules to cells, and lead, when not corrected, to progression of disease. Here

we will outline some characterizing bifurcation points in the dynamic progression of diseases,

summarizing and updating a theory that was extensively reported elsewhere.85-87

According to

conventional diagnostic criteria, what usually appears as the "disease" is actually the last phase,

7

consisting of particular biochemical and anatomical abnormalities. Prior to this, however, there are at

least three other phases. We have the very first phase in which an initial disorder, largely non-apparent

apart from a few very indistinct symptoms or variations in very subtle parameters, makes the body

susceptible to perturbation-induced external agents. This stage could for example include people who

are subject to overwork (stress) or to an unbalanced diet, or those who smoke, are exposed to low doses

of ionizing radiation, or present particular genetic characteristics that make them "at risk". Clearly, at

this level the balance between normal and pathological is extremely precarious, and the ensuing course

of the disease can come down on one side or the other, according to shifts in minor factors.

A second bifurcation can be found in the reactive phase of homeodynamic biological systems

(haemostasis, inflammation, tissue regeneration, etc.). These systems are "two-faced", in the sense that

they bring about healing but may also cause damage, because they can either attack or disorder the host

itself. To what extent, in each individual case, the damage done prevails over the reinstatement of

health, or vice versa, depends on subtle variations in the behaviour of the homeostatic system itself. In

particular, the fate of the reaction depends on the choice that the system has to make between the "price

to pay", in terms of toxicity and suffering, and the guarantee of success of the operation in terms of

survival of the body. A choice of this type depends both on the local elements involved (receptors,

concentration of mediators, presence of exogenous chemical substances) and on the type of centralized

control system that coordinates and regulates the various responses. Thus, at the level of this

bifurcation, the outcome of the reaction may depend on subtle factors that are significant for the

coordination of the reactions.

A third phase in the disease process, which represents another critical decision point, is when the

reactive systems fail to cope with the situation and to restore the original state. At this point a

pathological adaptation may set in, meaning a semi-permanent modification which shifts the receptor

sensitivity thresholds and induces further biochemical and anatomical changes. Chronic pathology

(“miasms” in homeopathic terms) is a dangerous form of adaptation, which make it possible to “live

with” the homeodynamic disorder, but also open up the way to progression. In fact, a chronically

disordered system requires high energy consumption and is more susceptible to further damage due to

lack of coordination in various defence and healing systems. Also, the choice between reaction and

adaptation is very complex, as it is determined by a multiplicity of subtle endogenous and exogenous

factors.

Amplification mechanisms

The “biological power” of a drug depends on the affinity between the binding site and the

molecule itself, as well as on the response of the treated system. Note that conventional drugs normally

act at concentrations between 10-6

M (micromolar) and 10-9

M (nanomolar), whereas the more modern

ones such as cytokines are also active at concentrations from 10-12

M (picomolar) to 10-15

M

(femtomolar). In the scientific literature, there are many works showing a clear biological efficacy

(meaning that there are demonstrable effects in laboratory systems) of substances diluted by as much as

10-18

M (attomolar), corresponding approximately to the 9C homeopathic dilution.1 The typical

physiological levels of the endogenous hormones are extremely low: 10–900 pg/ml for estradiol, 300–

10,000 pg/ml for testosterone, and 8–27 pg/ml for T4. When the circulating levels in blood are

corrected for the low fraction of the hormones that are not bound to serum binding proteins, the free

concentrations that actually bring about effects in cells are even lower, for example 0.1–9 pg/ml for

estradiol.88

A simple calculation illustrates how these doses pose a challenge to current theories: in fact, a

concentration of 10-15

M (approximately 5C-7C in homeopathic drugs, depending on the starting

concentration) corresponds to 109

(one billion) molecules per litre, which is also equivalent to 106 (one

million) molecules per cubic centimetre, or 1000 molecule per cubic millimetre. Taking blood as a

reference substance, it contains around 7000 leukocytes per cubic millimetre, meaning that in this case,

a 10-15

M solution would contain 1 molecule for every 7 cells. It is clear that the action of ULDs, which

contain very low doses of active substances, poses a challenge to pharmacology and claims the

existence of amplification mechanisms at some stage of the signal transmission chain, from molecules

in water environment to signal-receptor interaction and the wide range of transduction pathways. A

8

simplified scheme of some amplification steps at the level of receptors and signal transduction inside

the cell is depicted in Figure 1.

Figure 1. Example of possible signal amplification mechanisms at the cell level. It is not necessary

to involve many receptors to have a strong effect, nor is it necessary for the signal to be of a

molecular type. Receptor triggering or modulation could also be physicochemical (heat, radiation,

vibration, sound waves, or particular structures of water or solvent). cAMP: cyclic adenosine

monophosphate (activator of protein kinase A), Ad-5P: adenosine-5phosphate (hydrolysis

product of cAMP).

Receptors for signal molecules or for other types of messengers (light, electromagnetic signals,

stretching, action potentials) are highly plastic: the cells are capable of increasing (hypersensitivity,

priming) or decreasing (desensitization, tolerance, adaptation, down-regulation) the number of receptors

according to their needs, as well as of regulating their activity by modifying the affinity for the signal

molecule. On occasion, the cells may present more than one receptor for the same molecule, but with

different affinities and different intracellular effects.

The intracellular transduction systems couple receptor activation with production of signals or

activation of effector mechanisms; they are associated with enzyme activities, variations of intracellular

second messengers, modifications of membrane lipids and proteins, and the opening of ion channels.

Small changes of concentration and/or of oscillations frequency in second messengers like free calcium,

protons (H+), cyclic AMP and phospholipid derivatives can induce allosteric modifications of enzyme

functions, chain-reactions and cascades of intracellular signals, and eventually gene expression. The

multiform characteristics of the receptor and transduction systems are too vast topics to be dealt with

here. What is beyond doubt, however, is that the level of responsiveness is controlled at various levels

in the cell, that the sensitivity to external messages is modified during the course of disease, and that all

these mechanisms are susceptible to pharmacological modulation as well as by diet (e.g., the change of

membrane lipid composition, the role of antioxidants, the epigenetic effects of food components).

In summary, a few extracellular molecules or even a single molecule, or extremely low magnetic

fields can trigger (or regulate) a series of chain reactions that lead to the activation (or downgrading) of

9

the specific cell function related to that particular signal. According to this model, interaction between a

potentized homeopathic solution and the cell surface causes the membrane proteins, or their

glycosylated parts, to produce a cascade of biochemical events inside the cell resulting from contact

with the drug itself. Such events could be enormously amplified at the receptor and post-receptor level,

to even affect gene expression.18,89

We90,91

and others92-94

have previously illustrated how receptor

sensitization and desensitization, and in general the post-conditioning of cells by various types of

treatments, may support the beneficial effect of low dose stress compounds that are applied according to

the similia principle.

In the previous paper we cited the findings that silica nanostructures are formed during succussion in

glass containers which are usually employed in the preparation of homeopathic drugs.95

Recently Ives et

al.96

showed that boron, silicon, and sodium leaching from glass containers are present at micromolar

levels and have enzyme activity stabilizing effects. Moreover, the increased enzyme stability could be

mimicked in a dose-dependent manner by the addition of silicates to the enzyme assay. This finding

suggests a further mechanism of amplification of biologic effects of homeopathic drugs.

Stochastic resonance A further point linked to the ULD effects concerns resonance phenomena,

97,98 which are involved

in both information transfer and signal amplification. Stochastic resonance is a seemingly paradoxical

concept, according to which background noise (random fluctuations of energy and molecular vibrations

that disturb any natural system) may increase, rather than decrease, the perception of signals (see Figure

2). So, by this process, a system may become sensitive to stimulations so small that they would not

otherwise be perceived. In recent years, a series of experiments have shown that this phenomenon

occurs in lasers, superconductors, electronic circuits, neurons, and biological membranes.99,100

Figure 2. An intuitive illustration of stochastic resonance in plasma membrane. A: The glycocalyx

introduces a noise as an amplifier of signal-receptor interaction and increases the periodic signal

passed to the transduction systems. B: Upper diagram: A small periodic signal, with energy under

the activation threshld of receptor, produces no response. Intermediate diagram: Noise contain

no specific information and the receptor is not activated. Lower diagram: When the noise is

added to the signal, the activation energy exceeds the threshold and the system receives an

information with a frequency component equal to the periodic signal, but stronger than the pure

incoming signal.

Stochastic resonance requires a physical system capable of making transitions between two or

more states (oscillations), and of being perturbed by an input which can consist of an aperiodic "noise"

and of a periodic signal that is weak with respect to the noise. For example, stochastic resonance may

involve the membrane glycocalix which may introduce a noise as an amplifier of signal-receptor

interaction. When the noise of glycocalix oscillations is added to a (small) periodic signal, the periodic

10

oscillation is amplified, and at its output the system emits a signal with a frequency component equal to

the periodic signal, but stronger than the same incoming signal.

The membrane potential is a source of electromagnetic noise generated by continuous vibrations of

charges and molecular bonds, and by fluctuations in the dynamics of ion channels. The lipid-water

interfaces are transition regions with a very refined electrical structure, and highly sensitive to electric

fields so that even the slightest change in their electrical properties has an impact on the structure and

the oligomerization state (aggregation function) of proteins in the same membrane.101

Thus there is a

non-linear relationship between the incoming signal (input) and the transmitted signal (output): when

the input drops below a given threshold value, there is no output at all. On the other hand, a very weak

signal can be elevated above the threshold when it encounters the right amount of noise, and enters into

resonance with it; i.e., the signal encounters a resonance that can amplify it to an appropriate level for

the transmission. Also intracellular events such calcium oscillations, are increased by background

metabolic noise.102

The role of water Membrane proteins interact not only with signal molecules but also with water molecules and

clusters, a phenomenon that leads to protein conformational change and transient proton-transfer.103

This leads to the hypothesis that biological effects of HDs can also be mediated by transmission of

electromagnetic energy (and information) through water, using the ultra-fast and extremely efficient

transfer of energy, as exemplified in Figure 3.

Figure 3. Schematic representation of ultra-fast inter-molecular energy transfer in water by

excitation of O-H bond. Free adaptation of evidence provided by Nitzan and Woutersen.104,105

Chains of water molecules facilitate proton transfer within hydrophobic proteins. Since this occurs

at an intermediate conformation only, the rearrangement of protein-bound water molecules, from

inactive positions in the ground state to an active chain in an intermediate state, appears to provide

insight into proton-transfer mechanisms and functions of ubiquitous membrane spanning proteins.103

The Grotthus mechanism also works in so-called ‘‘water wires’’ that enable hopping of protons through

trans-membrane proteins such as bacteriorhodopsin that function as a proton pump.108

Such “supramolecular” organization of water in chains is similar to the proton “hopping”

mechanism proposed by Grotthus,106

and may account for amplification of effects of drug molecules

dissolved in water. An indirect confirmation that this may account for some activity of HDs is the

11

increase of electrical conductivity of highly diluted/succussed solutions reported by Elia.107

When an

H+ ion encounters a water molecule in a favourable geometrical position, it forms a bond with the water

molecule which in its turn releases an H+ ion. Thus, it is effectively as if ions that encounter a water

molecule (which enables this "hop") diffuse faster than ions which do not meet a water molecule in this

favourable geometrical position. Variations in the supramolecular structure of water may augment the

contribution of the hopping mechanism and hence the resultant diffusion of ions, thereby also

increasing specific conductivity.

Information transfer

The transmission of drug information from remedies of low and medium potency (ULDs) to body

target systems can occur through molecular interactions, regulated by affinity and concentration, as in

conventional drugs. Compounds can interact with local receptors (e.g. in the mouth or on the skin) or be

absorbed by mouth or intestine and transported to their targets through biologic fluids like blood and

lymph. On the other hand, it is conceivable that HDs can use different pathways of signal transmission,

like body water, nerve impulses, solitons, or even electromagnetic pathways. We call these pathways of

signal transmission as “meta-molecular” since they may require molecular movements and changes, but

are not restricted to them. Use of HDs is a tentative approach to the bioenergetic regulation of the

human body on a physical-biochemical interface, made possible by the extreme sensitivity of biological

systems to this type of regulation.

Biophysical interactions There is no single unitary explanation for the action of HDs on the organism, however an

accumulation of evidence from various fields of science is building up a conceivable and plausible

picture, in which biophysics is integrated with molecular biology and system biology. If the problem is

couched in physical and not merely in chemical terms, it is very likely that any such explanation must

necessarily take into account the sensitivity of living systems to small energies like those carried by

electromagnetic fields.109,110

In this context, the emerging bioelectromagnetic paradigm will have an

important role because it re-evaluates an important form of long-range communication, not only at

inter-molecular but also at supra-molecular levels of organization of biological systems.

Cells are able to detect and respond to weak electric and magnetic fields, possibly through

glycoprotein bound to ionic channels.111

Several molecular systems have been shown to be sensitive to

EM fields, even of very low intensity: photoreceptors (eye and skin), chlorophyll, G-Protein-coupled

trans-membrane receptors, cAMP-dependent protein kinase, heat-shock proteins, chromosomes,

Na+/K+ ATPase, lysozyme, membrane ionic channels and even water itself. Cells are detectors of very

weak periodic magnetic fields at around 10-3

volts/cm intensity, but in specific frequency “windows”,

i.e. where certain responses occur only within a restricted frequency band, the minimum intensity,

necessary to trigger the cell response, may be several orders of magnitude lower (10-6

volts/cm).112

On

the other hand, in living systems there are a number of sources of EM fields: electrical activities of

nervous centres and heart, charge movements (ions) in vessels, charge movements (ions, H+) inside

cells, membrane polarization/depolarization, electron-transport and proton-transport chains in

mitochondria, proton jumping in water and proteins, oxidation-reduction metabolic activities,

phosphorylation/dephosphorylation processes, enzymes that generate chemiluminescence, release of

biophotons by DNA, muscle contraction, piezoelectric activity (on bending) of bone, connective fibres,

microtubules, and microfilaments. Although many of these electrical events may be by-products of

metabolic activities without any specific function, the widespread EM sensitivity of sensing and

transduction systems suggest that they are also utilized as signalling modes for communication and

coordination among cells and tissues.

Practically all organisms emit light at a rate from few photons per cell per day to several hundred

photons per organism per second. This emission of “biophotons”, as they are called, is distinct from the

chemiluminescence of leukocytes or the bioluminescence of fireflies, which is associated with specific

organelles. Biophotons emission occurs at very low intensity but is universal to living organisms, where

it is thought to represent a long-range form of communication, capable of generating synchronous and

coherent phenomena. 113-115

DNA generates a longitudinal wave that propagates in the direction of the

magnetic field vector, and frequencies computed from the structure of DNA agree with those of the

predicted biophotonic radiation.116

The authors suggest that such a wave is able to use genetic code

12

chemically stored in the base pairs of the genes and to electrically modulate them, so as to "piggyback"

information from the cell nucleus to another cell. At the receiving end, the reverse process takes place

and the transported information is converted back into a chemical structure.

It has been suggested that acupuncture meridians are related to an interconnected cellular network

that regulates growth and physiology117

and meridians can, at a certain extern, be compared with

pathways for the propagation of electronic excitation in the body, similar to optical waveguides along

which electromagnetic pulses propagate as solitons.118

This theory may explain the high electric

conductance of the meridian system, and electrodermal activity may be a valuable physiological marker

for the acupuncture phenomenon.119,120

A review of the current progress in understanding coherence effects in relation to the mechanisms

of homeopathy and acupuncture, and of how bio-information may be stored in water has been published

by Smith.121

The author concludes that living systems interact with external electromagnetic fields in

such a way that it should be possible to control chemical reactions both in vitro and in vivo through the

interaction of the magnetic vector potential with the chemical potential. Electromagnetic fields have a

long range and then are able to produce recognition at a distance, also in a crowd of non-resonating

molecules. Long-range electromagnetic communication between molecules may represent the founding

theory able to unravel the nature of the molecular signal and the role of perimolecular water in its

transmission.122

Electronic transfer of information There is mounting experimental evidence that biological information capable of modulating

cellular behaviour and responses can be transferred by electronic means. The results of “digital biology”

suggest an electromagnetic nature for the molecular signal, heretofore unknown. This signal, that is

"memorized" and then carried by water, most likely enables in vivo transmission of the specific

molecular information between two functional biomolecules.122

In one study, neutrophils placed on one coil of an oscillator were activated by phorbol ester placed

on another coil, suggesting that molecules emit signals that can be transferred to neutrophils by artificial

physical means.123

Intriguing experiments evaluated cell proliferation rate and morphology in two

different cell populations seeded in separate polystyrene culture dishes incubated one above the other:

cell activities were different depending on whether there was a disk of black paper to separate the

different dishes, suggesting that specific signals emitted by the cells were transmitted through the

polystyrene wall.124

Others reported an electrical transfer phenomenon using a device made by a glass

test tube filled with distilled water (intended as receiver) and a quartz test tube with a source compound

(Amanita muscaria dust, magnesium sulphate).125

Two solutions were connected by a high voltage field

pulse for 15 minutes, then the exposure of biological systems (cress germinating seeds, E. Coli bacteria)

to such electrically-treated water caused a growth inhibition of the tested cultures.

The notion that organisms have mechanisms for generating biologically useful electrical signals is

not new, but the modern version is that magnetic fields act in conjunction with ion cyclotron resonance

(ICR), to regulate and transmit biological and pharmacological information within living systems. ICR

predicts effects by small ions involved in biological processes, which occur in definite frequency- and

intensity ranges ("windows") of simultaneously impacting magnetic and electromagnetic fields.126,127

According to Liboff, changes in human body impedance are significantly altered during exposure to

ICR and sinusoidal magnetic field combinations and protein peptide bonds are broken by ICR fields at

ultra-low magnetic intensities (0.05 muT).128

Investigating the phenomenon of resonant signalling, it

has been reported that exposure of human epithelial cell to ICR, generated by a commercial

electromedical device tuned to calcium ion at 7 Hz, acts as a cell differentiation factor.129

Furthermore,

it has been observed that specific frequencies modulate cell function and therefore can help restore or

maintain health.130

The phenomenon of “digitization” of biological signals was reported by Benveniste123

and recently

confirmed,131-135

, with the exception of another group,136

. In brief, Montagnier and co-workers

demonstrated the ability of some bacterial DNA sequences to induce electromagnetic waves at HDs in

water. A solenoid captured the magnetic component of the waves produced by the DNA solution in a

plastic tube, converting the signals into an electric current. This current was then amplified and finally

analysed on a laptop computer using specific software. Each dilution was followed by strong agitation

and this step was found to be critical for the generation of signals. Such signals appear to be a

“resonance phenomenon” triggered by the ambient electromagnetic background of very low frequency

13

waves.132

Interestingly, the genomic DNA of most pathogenic bacteria contain sequences that are able

to generate such signals, suggesting that a highly sensitive detection system might be developed for

chronic bacterial infections in human and animal diseases. A second paper followed up this suggestion,

showing that it is indeed possible to detect the presence of HIV DNA even when the RNA of the virus

has disappeared from the blood of HIV-infected people undergoing antiviral therapy.133

Recent investigations showed that retinoic acid (a neuronal differentiating agent), placed on one

coil attached to an oscillator, induced a decrease in cell growth, metabolic activity, and the protrusion of

a neurite-like structure in neuroblastoma cells incubated on another coil connected through an electronic

amplifier.134

If confirmed, these experimental results provide some evidence that the incubation medium

could be tuned in a resonant manner through a carrier frequency provided by the oscillator.135

Taken

together, these findings suggest that there are associated molecular signals that can be transferred to

target cells by physical means in a fashion that mimics the original molecules.

Water, nanoparticles and molecular interactions The importance of water to living processes derives not only from its ability to form hydrogen

bonds with other water molecules, but especially from its capacity to interact with various types of

biological molecules. Because of its polar nature, water readily interacts with other polar and charged

molecules such as acids, salts, sugars, and various regions of proteins and DNA. Recent advances in

theoretical methods, experimental techniques and brute computing power have made it possible to study

how water interacts with DNA, proteins and cells in unprecedented detail. Protein binding to specific

DNA sequences is a key element in various biological functions related to processing of genetic

information by regulating transcription, replication, and recombination. The mechanism of DNA

sequence discrimination, however, is still poorly understood.

Water is an essential participant in macromolecular binding and can contribute to recognition in

several ways. Complex formation is initiated by interactions between partners of protein-protein or

protein-DNA molecules with fully hydrated surfaces. During the process, specific bound waters are

expelled from the interface, leading to burial of the contact surfaces. However, a number of water

molecules may remain trapped at the interface and serve to mediate interactions between the

macromolecules. Interfacial water molecules in specific complexes not only act as linkers, but have also

been shown to buffer electrostatic repulsion between negatively charged groups of protein and DNA.137

The functioning of enzymes and protein folding is well known to be assisted by the surrounding

chaperoning water molecules, which are connected to the proteins via non-covalent, dynamically

changing chemical bonds. Water clusters have a key role in the light receptors of bacteria: on excitation

by light, retinal isomerization leads to a rearrangement of a water cluster that partly disconnects two

helices of the receptor. This hydrogen bond network proceeds further in later stages of conformation

transitions, altering tertiary structure and establishing the signalling state of the receptor.138

High-resolution protein ground-state structures of proton pumps and channels have revealed

internal protein-bound water molecules. Their possible active involvement in protein function has

recently come into focus. An illustration of the formation of a protonated protein-bound water cluster

that is actively involved in proton transfer was described for the membrane protein

bacteriorhodopsin.103

The authors showed that three protein-bound water molecules were rearranged by

a protein conformational change that resulted in a transient Grotthus-type proton-transfer chain

extending through a hydrophobic protein region. This discovery provides insight into proton-transfer

mechanisms through hydrophobic core regions of ubiquitous membrane spanning proteins such as G-

protein coupled receptors or cytochrome C oxidase.

The concept of aqueous nanodomains has been introduced to explain high potentization in

homeopathy. Simulations show that these long-lived nanodomains may interact with their targets, such

as inactive enzymes, converting them into the active form. This simple model omits many of the

complexities of a live organism but incorporates the essential elements of homeopathic action.139

Nanoparticles have unique biological and physicochemical properties, including increased catalytic

reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum

effects that are different from those of bulk-form materials.140

Enzyme regulation involves molecular

allosteric changes due to interaction with other molecules, phosphorylation/dephosphorylation of

specific amino acids, and complex formation. However, all these events occur in a surrounding non-

covalent intracellular network made up of water molecules. These water molecules do not just play a

part in solvation, but also function as chaperone catalysts participating in the regulation of chemical

14

changes in living cells. A “water-regulated cycle” consisting of this type of intracellular network of

weak non-covalent connections may be presumed to exist in living cells.141

An intuitive sketch of how a

water cluster could alter the conformation of a target protein is shown in Figure 4.

Figure 4. Scheme of how a water cluster may change a protein conformation by breaking internal

hydrogen bonds.

Water and gene expression DNA recognition by proteins involves a subtle interplay between direct protein-DNA interaction

and the indirect contribution from water and ions. The structure and energetics of water at the protein-

DNA interface show that water distributions exhibit sequence-dependent variations, suggesting that

interfacial waters can serve as a ‘‘hydration fingerprint’’ of a given DNA sequence.137

The double helix

structure, the strength of the hydrogen bonds, and even the DNA volume tend to change with increasing

water content. The bound water sheath is not just an integral part of such structures. It can also perform

a precise switching function, because results indicate that increasing the hydration shell by only two

water molecules per phosphate group may cause the DNA structure to "fold" instantly.142

High-

resolution crystal structures of the DNA duplex sequence reveal a highly-conserved cluster of eleven

linked water molecules, positioned in the minor groove. This cluster appears to have a key structural

role in stabilizing the non-covalent binding of small molecules. and in mediating between ligands and

DNA by means of an array of hydrogen bonds.143

An interesting view of how coherence domains postulated by quantum electrodynamics theory

may interact with biochemical pathways, has been recently proposed.144

When the energy stored in the

electromagnetic field of a coherence domain becomes equal to (resonates with) the activation energy of

a specific non-aqueous molecule, the coherence domain discharges its energy to perform a specific

reaction (coupling of electromagnetic and chemical modes).

15

Resonance and drug effects A further concept linking homeopathy with a biophysical perspective is that disease may be

regarded not only as a functional or molecular-structural abnormality, as in the classical view, but also

(and not by way of contrast) as a disturbance of an entire network of electromagnetic communication.

Such a network is based on long-range interactions between elements (molecules, nerve centres, organs,

to mention but a few) which oscillate at frequencies that are coherent and specific, and so capable of

resonance. The disease processes, besides causing quantitative and qualitative molecular alterations,

involve a disturbance of the bioelectric harmony and coherence of the body, of oscillation frequencies

and of the communications associated with them. If this is the case, it should be possible to bring these

alterations back to a state of equilibrium by means of “tuning”, i.e., by a change in frequency imposed

by resonant interaction with another oscillator. According to this notion, the homeopathic remedy might

act upon the patient as an external guiding frequency.

On this basis, a hypothetical model of the possible action mechanism of homeopathic drugs can be

advanced (see figure 5). A potentized homeopathic drug might be regarded as a small amount of matter

containing elements oscillating in phase (coherently), which are capable of transmitting these

oscillatory frequencies, via a process of resonance, to biological fluids (in turn mostly made up of

water), but also to complex "metastable" structures. These structures (macromolecules, a-helixes,

membranes, filamentous structures, receptors) are subject to nonlinear behaviour patterns and are

capable in their turn of oscillating.

Figure 5. Hypothetical model of various ways of biological communication. A: classic molecule-

receptor interactions, B: resonance interactin between water nanodomains and cell membrane

receptors and/or DNA, C: classic biophysical regulation of receptor responses. The water

nanodomain is formed by water molecules oscillating in phase, where oxygen is represented by

red spheres and hydrogen by blue spheres. For details concerning the physicochemical nature of

homeopathic remedies see the previous paper.1

16

There is thus the possibility of a resonance link forming between drug frequencies and oscillators

present in the living organism perturbed by disease. The nanoparticulate water clusters or CDs would

thus not act by “conventional” molecular interactions based on mass law, but rather by modulating

through resonance interactions the internal electromagnetic communications whose energy is provided

by the cell metabolism.145

The electromagnetic hypothesis of homeopathic drug action is very attractive but, at the present

state of knowledge, is mainly speculative and is awaiting physical or mathematical formalism.

Information transmission phenomena require resonances between oscillators of close frequencies

(eventually between harmonics). There are many orders of magnitude between the frequencies of

molecular vibrations (> 1013

Hz) and, for example, the EM signals emitted by high dilutions of DNA

(1000-3000 Hz).132,133

How can those relatively low frequency waves of DNA solutions modulate high

molecular frequencies responsible for specific biochemical reactions remains to be clarified, even if

some hypothesis has been put forward by the authors.131

The inversion of effects (the “simile”)

According to the homeopathic law of similia, the remedy able to positively regulate a diseased

organism (personalised homeopathic treatment) is the same substance that elicits similar symptoms in a

healthy organism. The homeopathic pharmacopoeia was developed through careful testing of hundreds

of substances on healthy people to detect their specific and global perturbation power. This was the first

systematic application of pharmacological experimentation in the history of medicine, and it continues

to this day.

The various theories of the simile have been described in previous papers.90,91,146,147

The

characteristic “therapeutic similarity” in drug action purported by homeopathy may be fundamentally

based on the widespread phenomenon of inversion of biological effects dependent on the following

factors: a) the dose utilized and absorbed, b) the time or schedule of administration, c) the physiological

state of the receiver/target system. A combination of one or more of these factors and the contribution

of complexity science give rise to a consistent theory of the homeopathic “simile” effect.91,147

Hormesis Currently, efficacy is intuitively regarded as being higher when more molecules of drug reach the

target (receptor, enzyme), but this approximation is largely incorrect because dose-response curves are

often non-linear and even paradoxical. There is a widespread occurrence of low molecular dose effects

that appear to be opposite to those caused by high molecular doses, as seen in hormesis. Moreover, in

vivo acute and chronic effects of drugs are often opposite in their effects, an observation that some

authors have suggested could be exploited using conventional drugs148-150

or homeopathic remedies 151

.

Various authors have suggested that hormetic phenomena can provide a framework for

interpreting homeopathic effects, at least insofar as low dilutions, rather than HDs, are concerned.91,152-

157 Inverse (or “paradoxical”) effects of drugs or of biologically active compounds on specific target

systems can be often observed by changing the concentrations or the doses of the compound: for

example, low doses of a toxic compound may be stimulatory, high doses may be inhibitory (as we will

see later, also the opposite may be possible, according to the experimental systems employed). In

general these effects, formerly described in the “Arndt-Schulz rule”,158,159,160

can be documented by the

finding of inverted U-shaped curve of dose-response. Endpoints displaying this curve include growth,

fecundity, and longevity. Another possibility is to find a time-course of an intoxication experiment

where high dose causes progressive death of biological system, while a low dose causes an initial

decrease of viability, followed by a recovery (rebound) and an increase over the basal levels.

Despite the substantial development and publication of highly reproducible toxicological data, the

concept of hormetic dose-response relationships was not integrated into the mainstream of toxicological

thought until recent years.161

This phenomenon is now well recognized, with a number of explanation at

the molecular level (e.g. different receptors for the same substance having different ligand affinities and

triggering transduction pathways) and in immunology, where the systemic and local responses are

known to depend on the dose in a complex way (e.g. foreign antigens may sensitize the host but low

doses of the same substance may suppress the system if administered by oral route). The term

“postconditioning hormesis‟ was introduced to indicate the phenomenon where small stimuli exert a

beneficial effect when applied to cells or organisms which previously experienced a severe harmful

17

stress.162

As an example, a low level of hypoxic stress was applied subsequent to myocardial infarction,

which reduced the cellular damage.

Tables 2 and 3 summarize several examples of inverse effects according to the dose in laboratory

systems and in animal models respectively.

Without going into many details, the paradox of arsenic can be mentioned as an example. This

mineral is a well-documented carcinogen that also appears to be a valuable therapeutic tool in cancer

treatment.216

In this context, the research line of the group of Van Wijk and coworkers is worthy of

citation.93,152,152,217

Table 2. Examples of inverse effects in laboratory systems

System Agent First effect Inverse effect

Yeast163

Heavy Metals Block growth Low doses increase growth

Leukocytes164

Cytostatic agents Cytotoxicity Low doses stimulate growth

and phagocytosis

Fibroblasts165-167

Arsenite

Cadmium Cell toxicity

Low doses protect from

toxicity or stimulate DNA

synthesis

Neurons168,169

Naloxone Antagonizes morphine Low doses enhance the effect

of morphine

Epithelial cells

Tumor cells170

Oxidants

Short-term/high doses

decrease viability

Long-term/low doses increase

viability

Platelets148,171 Diclofenac High doses stimulate

adhesion Low doses inhibit adhesion

Leukocytes146,172

Bacterial peptides Stimulate adherence Low doses inhibit adherence

Leukocytes173

Podophyllotoxin Cell toxicity Low doses enhance oxidative

metabolism

Wheat germ174-176

Arsenite Cell toxicity High dilutions protect from

toxicity

Lymphocytes177,178

Cadmium Cell toxicity High dilutions protect from

cadmium toxicity

Neurons179,180

Glutamate,

cycloheximide Neurotoxicity

Extremely low doses and high

dilutions protect from

neurotoxicity

Basophils14

Histamine Inflammation HDs inhibit basophil

activation

Basophils181

Quercetin Inhibit cell activation Low dose enhance fMLP-

induced activation

In response to proteotoxicity, cells react with an upregulation of heat shock proteins (hsps). These

proteins function primarily as molecular chaperones, facilitating the folding of other cellular proteins.

When cells were damaged with chemical compounds such as arsenic or cadmium and subsequently

exposed to low dose conditions of the same compounds, both hsps synthesis as well as defence and

survival capacity were enhanced (“homologous” simile). Low doses of arsenic were also able to

enhance survival of cells to a heat shock (exposure to temperatures >42.5 °C) (“heterologous” simile).

This line of research clearly demonstrates the biphasic action of a substance: a small dose can exert a

stimulatory effect on the recovery and the development of survival capacity of cells that have been

previously disturbed by a high dose of the same substance.

18

Table 3. Examples of inverse effects in animal models

System Agent First effect Inverse effect

Tadpoles (frogs) 20,21,182,183

Thyroxine Stimulates metamorphosis

High dilutions inhibit

metamorphosis

Rat blood184-186

Acetylsalicylic

acid

Inhibit platelet aggregation

and hemostasis

Very-low doses have

thrombogenic activity

Dog heart187

Ischemia Causes infarction Ischemic preconditioning

protects from infarction

Mice kidney188

Free radicals Toxicity Pre-treatment with low doses

protect from toxicity

Mouse prostate189

Estrogens Inhibit growth Low doses promote growth

Mouse and rat

immune

system190,191

Protein antigens Induce allergy autoimmune

disease

Oral administration protects

and cure autoimmunity

Mice192

Morphine Antinociceptive effects Extremely low doses enhance

pain sensitivity

Rat arthritis193

Naloxone Hyperalgesia Low doses have

antinociceptive effects

Mice194,195

Naloxone Antagonizes morphine Analgesic effects in ultra-low

doses

Rat, guinea pig196-

201

Histamine and/or

bee venom Inflammation, oedema

Low doses and high dilutions

reduce inflammation

Rat liver202,203

Carbon

tetrachloride Toxicity

Low doses protect from liver

toxicity

Rat immune

system204-206

Mycobacteria in

adjuvant

Induce arthritis when

injected intra-paw

Intraperitoneal low-doses cure

arthritis

Mice, guinea pig,

rats207-211

Arsenic Liver toxicity, genotoxicity

Protection by ultra-low doses

of arsenic and increase of

arsenic elimination

Rat212,213

Carcinogens

(acetaminofluoren

e, phenobarbital)

Induce cancer Low doses protect from

cancer

Rat214

Bacillus antracis Severe inflammation and

death

Low doses of bacillus extract

protect from toxicity

Mice215

Gelsemium

sempervirens

Causes severe weakness,

dizziness, convulsions

High dilutions are anxiolytic

and increase exploration

movement

19

It is of interest that this stimulatory effect of low dose stress is dependent on the initial exposure

condition: the more severe the initial stress conditions, the smaller the concentration required for

stimulating survival and hsps induction.

Our group has given several contributions in this field, like the demonstrations that bacterial

peptides (leukocyte receptor agonists with powerful stimulating activity on leukocyte metabolism and

adhesiveness) have inhibitory effects on leukocyte adhesion when used at low doses.172,218

This

paradoxical effect of low-dose peptides is probably due to the “gating” exerted by cyclic AMP at the

level of intracellular signal transduction pathways.146,219

Furthermore, we showed that human platelets

are inhibited by low doses and stimulated by high doses of non-steroidal anti-inflammatory

drugs148,171

and that podophyllotoxin inhibits leukocyte metabolism when administered at high doses

while it exerts a stimulating role (priming) at low doses.173

These observations are in the framework of

the hormesis concept.

Although the inversion of effects is often observed on changing the doses (or

dilution/dynamization steps in homeopathic terms), this is not a general rule. Others have reported that

Ruta, Thuja, Hydrastis and Carcinosinum have cytotoxic and apoptosis-inducing effects on several cell

cultures, even at homeopathic doses.220,221

In animal models, silica (which is a stimulant of

macrophages and fibrous tissue formation at high doses) stimulates tissue healing and macrophage

activation also at extremely low (homeopathic) doses.33,34

We have observed181

that quercetin, a natural

compound contained in fruits and vegetables, exhibits a “inverted-U shaped” dose-response curve

(stimulation at low doses, inhibition at high doses) when human basophils are stimulated by bacterial

peptides. However, when the cells are stimulated by anti-IgE antibodies (mimicking an allergic

reaction) the inhibition exerted by quercetin is observed both at low and at high doses, the effects being

proportional to the dose utilized. Regarding the effects in animal models, the studies from the group of Doutremepuich deserve

citation. Starting from the observation that platelet aggregation on whole blood was stimulated after

administration of ultra-low dosage acetylsalicylic acid in healthy volunteers,222

they extensively

investigated these effects in a rat model of thrombus formation.184-186

A partial occlusion was induced in

small mesenteric vessels by an argon laser. The laser induced damage of endothelial cells and thrombi

formed within seconds after the laser lesion and grew rapidly. Embolization began during the minute

following the laser injury. Compared to placebo, the administration of acetylsalicylic acid at ultra-low

doses induced an increase in number of emboli and in the duration of embolization. These findings are

highly paradoxical because the “conventional” pharmacological effect of acetylsalicylic acid would be

to inhibit platelet aggregation and thrombus formation. Also paradoxical pro-inflammatory, pro-

thrombotic effects associated with chronic use of anti-inflammatory agents have been described.223

These effects are attributable to compensatory host response rather than direct effects of the drugs.

At Verona University we explored the applications of similia principle in various animal models.

The first one showed that high dilutions of histamine are able of modulating the inflammation caused

by high doses of histamine in rats.198

A second rat model was developed by our group, showing that

injection of low doses of immune adjuvant (based on killed Mycobacterium butyricum, Mb) into the

peritoneum of rats is capable of preventing and curing the arthritis induced by the injection of high

doses of the same adjuvant into the paw.205

. Local injection of low doses of Mb at 3rd and 10th day

after adjuvant arthritis induction is correlated with suppression of primary and secondary lesions of

disease, decrease of inflammatory cytokines like IL-6, increase of anti-Mb antibodies, increase of

nitrite/nitrate serum levels and growth of regulatory peritoneal cells.206

This kind of immunoregulation

by the “simile” (“isopathic” approach according to the traditional terminology) is coherent with several

other lines of evidence obtained in animals and in humans.91,160,191

Others have questioned whether there is a direct link between homeopathy and hormesis, arguing

that homeopathy is a highly individualized therapeutic system, that homeopathic concentrations are

often far below the Avogadro number and that hormetic substances do not require any special

preparation.224

. The relationship between hormesis and homeopathy has been recently discussed in a

full issue of Human and Experimental Toxicology. As we90,91

and others156

have pointed out, hormesis

is the name given to experimental evidence of certain apparently paradoxical phenomena, but does not

itself constitute any sort of explanatory theory, least of all for homeopathy. Each example of a hormetic

curve can be explained by one or more mechanisms, which are today being explored with ever greater

detail and thoroughness: transduction of extracellular signals into intracellular messages, cellular and

tissue repair systems, control of cell growth and apoptosis, genetic and epigenetic molecular changes. In

20

any case, the traditional hormesis concept applies only to molecular “doses”, that is to concentrations

from zero (no effect, taken as a control) upward; homeopathy also employs very high

dilutions/dynamizations that in theory do not contain a single molecule of the original active substance.

Paradoxical pharmacology and rebound effects Inverse (or “paradoxical”) effects of drugs or of biologically active compounds on specific target

systems can be often observed by changing the time or duration of the application of the treatment and

the observation period. For example, short treatment may be stimulatory, long lasting application may

be inhibitory (also the opposite may be possible, according to the experimental systems employed).

This field includes rebound effects (reversal on withdrawal) and paradoxical pharmacology. One

possible general hypothesis for why paradoxical pharmacology might work is the difference between

the chronic versus the acute effect of drugs.91,149,150

It has been suggested151,225,226

that even modern

drugs can be utilized according to the principle of homeopathic cure, employing the rebound effect as a

curative reaction. It would be possible to compile a Materia Medica that would group the symptoms

produced by rebound effects of the medications in human individuals, utilising them, a posteriori,

following a partial or total similitude, in minimal or ponderous doses. By doing that, it should be

possible to take advantage of the modern pharmacological experimentations either in healthy

individuals (phase 1 trials) or in ill people (phase 2-3 trials), thus amplifying the spectrum of

homeopathic cure with a wide range of new symptoms and medications.

Finally, inverse effects of drugs, or of biologically active compounds, on specific target systems

can be often observed by changing the physiological state or the susceptibility conditions of the system

itself: for example, the same compound may cause stimulatory, growth-promoting effects on a

healthy/unperturbed system and inhibitory, suppressing effects of the same variable when applied to the

diseased/previously perturbed system (also the opposite may be possible, according to the experimental

systems employed). This field includes the “initial value rule of Wilder”227,228

and other widely

documented pharmacological phenomena.91

In summary, the applications of the “simile” principle – interpreted as inversion of biological and

pharmacological effects of active compounds according to the dose and/or the sensitivity of the target

system - are widespread and consistent: stimulation or protection by low doses of toxic compounds

(typical hormesis effect) on cell and animal models, regulation of specific cellular activities by low

doses of stimulating compounds, inhibition or protection of autoimmunity by low doses of antigen, and

paradoxical effects of drugs. Within the framework of our current knowledge of living systems and

modern investigational techniques, it will be possible to reformulate the ancient principle with the aim

of constructing reasonable models that can be tested at different biological levels, from cells to human

beings.

Systems biology In dynamic systems that are far from thermal equilibrium, minimal variations in the internal or

ambient conditions (such as those induced by even a very small oscillatory resonance) may play a

decisive part in the ensuing evolution of the system itself. In a variety of systems, the "butterfly

effect"229

may be used to control chaos, on condition that the parameters to be controlled and changed

are well known.230-233

Systems at any level (e.g., physical, biological, social, ecological) are open to

information, energy, and matter to varying degrees, and therefore interact with other systems to varying

degrees.234

The dynamic interaction of systems in mutual recurrent feedback relationships naturally

create resonance and synchronizations, such as those between heart and brain.235

Those interactions

over time create memory in homeodynamic systems. The logic of recurrent feedback loops, which

applies to all dynamical network systems, leaded to the systemic memory hypothesis, applied to high-

dilution therapies.98

Based on microarray data, it has been suggested that gene regulatory networks may be regarded as

dynamically ‘critical’ systems poised near the phase transition between order and chaos,233,236

where

extreme sensitivity to initial conditions and small perturbations is well known to occur. Genetic

regulatory networks may be the target of HDs message by virtue of their flexibility in response to

environmental stimuli.236

According to this argument, the highly diluted drug might be regarded as a

complex solution endowed with nanoparticulate structures capable of communicating some

pharmacological information, through a resonance process, to biological fluids and to critical cell

systems such as macromolecules, alpha-helixes, filamentous structures, receptors, and DNA networks.

This effect could be mediated by the participation of a dynamic intracellular water network which may

21

be presumed to exist in living cells.141

Chaotic regimes have been found in a number of physiological

systems, including heart and neural systems,237-240

and this would result in enhanced susceptibility to

extremely low energy inputs and to small changes of regulatory factors. The mechanism suggested

above is in line with findings that homeopathic effects in humans can be detected through sensitive

evaluation of heart rate variability.76,241

The working hypothesis is that the homeopathic remedy, containing small amounts of the original

substance - or its information imprinted in the solution by dilution and succussion - possesses a high

“information content” targeted for a specific case, by virtue of the similarity between the patient’s

symptoms and those ascribed to the remedy (law of similarity). This information content, acting on a

system in critically sensitive conditions, is able to guide it toward a particular behaviour, somewhat like

a “catalyzer of order” or a “pacemaker” that moves the system away from a pathological attractor and

redirects it toward a physiological attractor.

In short, the remedy selected based on homeopathic principles can be perceived by the various

regulation systems--which have a crucial role in the dynamics of the pathology--as an exogenous signal

that affects particularly active receptors, enzymes or genetic networks. The “similarity” enables drug

information to interact with endogenous targets that have lost their regulatory capacity due to

homeodynamic blockages (pathological adaptations) and changes of attractors (miasms).242-244

Precisely

because it “touches” extremely sensitive points (bifurcations), the target signal, even with minimal

energy, can trigger a homeodynamic reaction that shifts the global imbalance of the sick person towards

a new dynamic attractor, closer to the state of health.

The specificity of the information can be ascribed to sensitizing (priming) of the receptor system

as a result of antecedent biological stress, to the fact that using low doses or HDs only touches certain

particular systems, and finally to the complexity of corrective actions at various levels. In acute

diseases, homeopathic regulation can be considered a “regulation” in the sense that it abates the

counterproductive excesses of the reactions themselves, while in chronic disease it can be regarded as

“unblocking” pathological adaptations and redirecting the organism toward correct responses. Others

have suggested that refocusing attention on the dynamics of the patient as a nonlinear complex system

could help account for similar effects of various forms of natural medicine in the healing process of the

person as a unified whole.245-248

Updating the designation from "homeopathy" to "system regulation

therapy" would most adequately reflect the integration of this historical but controversial medical

system with modern scientific theories and findings.

Conclusions

The rational view of the pharmacodynamic activity of homeopathic drugs can thus be set forth as

follows:

1. Natural diseases are a consequence of perturbations of molecular and bioelectrodynamic networks

at the various levels of biological organization; the healing or progression of a disease depends on

the systemic and dynamic rules of the affected networks, which determine the reactions and/or

adaptation to those perturbations.

2. ULDs and HDs of drugs may act on the information networks of the body, where electromagnetic

interactions and water clusters associated with proteins and DNA have a major role in the

coordination pathways for biochemical reactions, neuroimmunological control of body identity and

integrity, and even of psychological integrity.

3. A number of molecular, cellular and systemic targets of homeopathic drugs have been described in

laboratory model systems. These targets are highly sensitive to drug regulation thanks to powerful

amplification mechanisms and to the participation of solvent (water) dynamics in information

transfer.

4. The medicine that has been chosen according to the similia principle may be perceived by specific

regulatory systems - that have a crucial role in the dynamic of the diseases - as specific signal which

may trigger a homeodynamic reaction that shifts the global disequilibrium of the ill person toward a

new dynamical behaviour, proximal to the healthy state.

5. The more sensitive a system is to a particular regulation, the lower should be the dose (or the

energy) required to regulate it in an effective way. Frequency information can be imprinted into a

22

water solution by succussion, in the form of coherent domains or nanoparticles. This is what creates

a homeopathic HD solution or potency.

Acknowledgements This work was supported by a grant from Boiron Laboratoires to Verona

University and from Italian Research Ministry. The authors declare that they have no conflict of interest

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